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Background: Adjuvant therapy is used to reduce the risk of hepatocellular carcinoma (HCC) recurrence and improve patient prognosis. Exploration of treatment strategies that are both efficacious and safe has been extensively performed in the recent years. Although donafenib has demonstrated good efficacy in the treatment of advanced HCC, its use as adjuvant therapy in HCC has not been reported. Objectives: To investigate the efficacy and safety of postoperative adjuvant donafenib treatment in patients with HCC at high-risk of recurrence. Design: Retrospective study. Methods: A total of 196 patients with HCC at high-risk of recurrence were included in this study. Of these, 49 received adjuvant donafenib treatment, while 147 did not. Survival outcomes and incidence of adverse events (AEs) in the donafenib-treated group were compared. Inverse probability of treatment weighting (IPTW) method was used. Results: The median follow-up duration was 21.8 months [interquartile range (IQR) 17.2–27.1]. Before IPTW, the donafenib-treated group exhibited a significantly higher 1-year recurrence-free survival (RFS) rate (83.7% versus 66.7%, p = 0.023) than the control group. Contrarily, no significant difference was observed in the 1-year overall survival (OS) rates between the two groups (97.8% versus 91.8%, p = 0.120). After IPTW, the 1-year RFS and OS rates (86.6% versus 64.8%, p = 0.004; 97.9% versus 89.5%, p = 0.043, respectively) were higher than those in the control group. Multivariate analysis revealed that postoperative adjuvant donafenib treatment was an independent protective factor for RFS. The median duration of adjuvant donafenib treatment was 13.6 (IQR, 10.7–18.1) months, with 44 patients (89.8%) experienced AEs, primarily grade 1–2 AEs. Conclusion: Postoperative adjuvant donafenib treatment effectively reduced early recurrence among patients with HCC at high-risk of recurrence, while exhibiting favorable safety and tolerability profile. However, these findings warrant further investigation. Plain language summary: Comparison of the outcomes of patients with HCC with or without donafenib after radical resection to better understand the efficacy and safety of postoperative adjuvant donafenib Why was this study done? Donafenib is the only new-generation targeted drug developed in the past 14 years that has demonstrated superior efficacy and increased safety in the first-line treatment of HCC. We aimed to explore whether postoperative adjuvant donafenib can improve the prognosis of patients with HCC at high-risk of recurrence. What did the researchers do? Medical data of patients with HCC at high-risk of recurrence who underwent radical resection at two medical centers between April 2021 and October 2022 were collected to compare long-term outcomes of patients treated with and without donafenib and explore the safety of adjuvant donafenib treatment. What did the researchers find? A total of 196 patients with HCC at high-risk of recurrence, including 49 who received adjuvant donafenib treatment and 147 who did not, were analyzed. At a median follow-up of 21.8 months, it was observed that adjuvant donafenib treatment effectively reduced early recurrence among patients with HCC at high-risk of recurrence, while exhibiting favorable safety and compliance profiles. What do the findings mean? The study provides real-world clinical empirical data on adjuvant donafenib treatment for patients with HCC at high-risk of recurrence, and these results may provide new directions for adjuvant treatment of HCC. [ABSTRACT FROM AUTHOR]

The N-reductive enzyme system (NRES), composed of MARC1, MARC2, CYB5, and CYB5R, is responsible for the reduction of N-oxygenated compounds and participates in several physiological processes. For example, MARC2 serves as an important prognostic indicator and is downregulated in hepatocellular carcinoma, and the downregulation of MARC2 is critical to the regulation of lipid metabolism and cell cycle progression. However, the role of MARC2 in tumor immune microenvironment modification had not previously been investigated. In this study, we found that downregulation of MARC2 was associated with the differentiation of CD4+T cells into regulatory T cells (Tregs). Furthermore, restoring the expression of MARC2 could increase the expression of HLA-C and B2M via PPARA-related lipid metabolism signaling pathways, which could facilitate tumor antigen presentation to the tumor-infiltrating T cells. Additionally, MARC2 expression negatively correlated with several immune checkpoints. The immune checkpoint burden was generated based on 28 MARC2-related immune checkpoints. Patients with a higher immune checkpoint burden were predicted to have a poorer prognosis and a lower level of activated CD8+ T cells. The results showed that expression of the NRES is a prognostic indicator of hepatocellular carcinoma and MARC2 contributes significantly to predict the prognosis. Finally, loss of MARC2 in HCC patients was found to facilitate immune escape and was associated with immunosuppression. [ABSTRACT FROM AUTHOR]

Cystatin SN, a specific cysteine protease inhibitor, is thought to be involved in various malignant tumors. Therefore, we evaluated the role of cystatin SN in hepatocellular carcinoma (HCC). Notably, cystatin SN was elevated in tumorous samples and cells. Moreover, overexpression of cystatin SN was correlated with tumor diameter and TNM stage. Cox multivariate analysis displayed that cystatin SN was an independent prognosis indicator and that high cystatin SN level was associated with a dismal prognosis. Moreover, cystatin SN enhancement facilitated the proliferation, migratory, and invasive potential of Huh7 and HCCLM3 cells, whereas cystatin SN knockdown caused the opposite effect. Cystatin SN also modulated the epithelial‐mesenchymal transition progression through the PI3K/AKT pathway. In vivo cystatin SN promoted HCCLM3 cell growth and metastasis in xenograft mice model. Thus, cystatin SN was involved in HCC progression and could be a latent target for HCC treatment. [ABSTRACT FROM AUTHOR]

The tumour microenvironment (TME) is a crucial mediator of cancer progression and therapeutic outcome. The TME subtype correlates with patient response to immunotherapy in multiple cancers. Most previous studies have focused on the role of different cellular components in the TME associated with immunotherapy efficacy. However, the specific structure of the TME and its role in immunotherapy efficacy remain largely unknown. We combined spatial transcriptomics with single-cell RNA-sequencing and multiplexed immunofluorescence to identify the specific spatial structures in the TME that determine the efficacy of immunotherapy in patients with hepatocellular carcinoma (HCC) receiving anti-PD-1 treatment. We identified a tumour immune barrier (TIB) structure, a spatial niche composed of SPP1 + macrophages and cancer-associated fibroblasts (CAFs) located near the tumour boundary, which is associated with the efficacy of immune checkpoint blockade. Furthermore, we dissected ligand‒receptor networks among malignant cells, SPP1 + macrophages, and CAFs; that is, the hypoxic microenvironment promotes SPP1 expression, and SPP1 + macrophages interact with CAFs to stimulate extracellular matrix remodelling and promote TIB structure formation, thereby limiting immune infiltration in the tumour core. Preclinically, the blockade of SPP1 or macrophage-specific deletion of Spp1 in mice led to enhanced efficacy of anti-PD-1 treatment in mouse liver cancer, accompanied by reduced CAF infiltration and increased cytotoxic T-cell infiltration. We identified that the TIB structure formed by the interaction of SPP1 + macrophages and CAFs is related to immunotherapy efficacy. Therefore, disruption of the TIB structure by blocking SPP1 may be considered a relevant therapeutic approach to enhance the therapeutic effect of immune checkpoint blockade in HCC. Only a limited number of patients with hepatocellular carcinoma (HCC) benefit from tumour immunotherapy, which significantly hinders its application. Herein, we used multiomics to identify the spatial structure of the tumour immune barrier (TIB), which is formed by the interaction of SPP1+ macrophages and cancer-associated fibroblasts in the HCC microenvironment. This structure constrains immunotherapy efficacy by limiting immune cell infiltration into malignant regions. Preclinically, we revealed that blocking SPP1 or macrophage-specific deletion of Spp1 in mice could destroy the TIB structure and sensitize HCC cells to immunotherapy. These results provide the first key steps towards finding more effective therapies for HCC and have implications for physicians, scientists, and drug developers in the field of HCC. [Display omitted] • Integration of multi-omics was used to identify a TIB (tumour immune barrier) structure in the HCC microenvironment. • This TIB structure contributes to the efficacy of immunotherapy. • SPP1 + macrophages and CAFs interact to promote the formation of the TIB structure and limit immune infiltration of tumours. • Blockade of SPP1 or macrophage-specific deletion of Spp1 in mice can destroy the TIB structure and sensitize HCC to immunotherapy. [ABSTRACT FROM AUTHOR]

To investigate the role and prognostic value of mH2A1 in the progression of hepatocellular carcinoma (HCC). Basing on the Cancer Genome Atlas-Liver Hepatocellular Carcinoma (TCGA-LIHC) and GEO datasets, the gene expression of mH2A1 and relative clinical characteristics were analyzed to assess the prognostic significant of mH2A1 in HCC. The protein expression of mH2A1 was measured by immunohistochemistry. Stable cell lines and nude mice model were used to investigate the role of mH2A1 in the progression of HCC. In this study, using TCGA-LIHC data and HCC tissue microarray, we found that expression of mH2A1 was higher in tumor tissues than in adjacent normal tissues. These results were validated using the GEO database. Patients with high levels of mH2A1 were predicted to have larger tumor size and more advanced tumor stage and grade. Multivariate analysis revealed that increased mH2A1 expression was an independent prognostic risk factor of shorter overall survival (OS). Experimental results showed that elevated mH2A1 expression promoted the progression of HCC while reduced mH2A1 expression lead to opposite effects in vitro and in vivo. mH2A1 promoted the progression of HCC by regulating cell cycle via AKT. Dysregulated expression of mH2A1 was associated with its DNA methylation status. Two CpG sites (cg01466741 and cg02614129) were negatively correlated with mH2A1 expression. Notably, high methylation of both CpG sites was associated with better OS. Based on the above results, we concluded that upregulated mH2A1 in HCC promoted tumor progression and could serve as an unfavorable prognostic indicator. • mH2A1 expression might serve as an independent prognostic risk factor of HCC. • mH2A1 promotes the progression of HCC by regulating cell cycle via AKT. • Dysregulated expression of mH2A1 in HCC tissue was associated with its DNA methylation status in HCC. [ABSTRACT FROM AUTHOR]